There is considerable interest in the role of polyunsaturated fatty acid oxygenation in malignant transformation. Release of arachidonic acid from phospholipids is an early response of cells to stimulation by hormones, proteinases, tumor promoters, etc. The liberated fatty acid is a substrate for oxygenases that catalyze the committed step in a casade that generates a wide variety of bioactive lipids. Free radicals and hydroperoxides are intermediates in this process, which provides a mechanism for conversion of extracellular recognition events to intracellular oxidation everts. My laboratory is attempting to elucidate the biochemical mechanisms by which polyunsaturated fatty acid oxygenation contributes to tumor initiation, promotion, and metastasis. The projects outlined in this application represent the major focus of our current efforts. We are conducting experiments to (1) determine the role of free radicals and hydroperoxides in tumor initiation and promotion, (2) define the role of DNA modification in the mutagenic activity of carbonyl compounds, and (3) explore the possibility that modulation of PGH synthase is an effective strategy for development of novel antimetastatic agents. Our approach is to exploit the unique chemical features of each biochemical event to develop novel methodologies that we can use to probe to probe relevant biological models.